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Targeting Mycobacterium tuberculosis CoaBC through Chemical Inhibition of 4'-Phosphopantothenoyl-l-cysteine Synthetase (CoaB) Activity
- Source :
- ACS Infectious Diseases
- Publication Year :
- 2021
- Publisher :
- American Chemical Society (ACS), 2021.
-
Abstract
- Coenzyme A (CoA) is a ubiquitous cofactor present in all living cells and estimated to be required for up to 9% of intracellular enzymatic reactions. Mycobacterium tuberculosis (Mtb) relies on its own ability to biosynthesize CoA to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the pathway to CoA biosynthesis is recognized as a potential source of novel tuberculosis drug targets. In prior work, we genetically validated CoaBC as a bactericidal drug target in Mtb in vitro and in vivo. Here, we describe the identification of compound 1f, a small molecule inhibitor of the 4′-phosphopantothenoyl-l-cysteine synthetase (PPCS; CoaB) domain of the bifunctional Mtb CoaBC, and show that this compound displays on-target activity in Mtb. Compound 1f was found to inhibit CoaBC uncompetitively with respect to 4′-phosphopantothenate, the substrate for the CoaB-catalyzed reaction. Furthermore, metabolomic profiling of wild-type Mtb H37Rv following exposure to compound 1f produced a signature consistent with perturbations in pantothenate and CoA biosynthesis. As the first report of a direct small molecule inhibitor of Mtb CoaBC displaying target-selective whole-cell activity, this study confirms the druggability of CoaBC and chemically validates this target.
- Subjects :
- 0301 basic medicine
Coenzyme A
030106 microbiology
Druggability
Article
Cofactor
Pantothenic Acid
drug discovery
Mycobacterium tuberculosis
03 medical and health sciences
chemistry.chemical_compound
In vivo
Cysteine
Peptide Synthases
biology
Drug discovery
Chemistry
biology.organism_classification
Small molecule
In vitro
3. Good health
030104 developmental biology
Infectious Diseases
Biochemistry
tuberculosis
biology.protein
CoaBC
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- ACS Infectious Diseases
- Accession number :
- edsair.doi.dedup.....8b118e20c165cc2ee3aa60e19f743440